Masuda Muneyuki, Suzui Masumi, Lim Jin T E, Deguchi Atsuko, Soh Jae-Won, Weinstein I Bernard
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, HHSC-1509, 701 W. 168th Street, New York, NY 10032, USA.
J Exp Ther Oncol. 2002 Nov-Dec;2(6):350-9. doi: 10.1046/j.1359-4117.2002.01062.x.
In a recent study on head and neck squamous cell carcinoma (HNSCC) cells we found that epigallocatechin-3-gallate (EGCG), a major biologically active component of green tea, inhibited activation of the epidermal growth factor receptor (EGFR) and related signaling pathways. Since activation of EGFR signaling pathways is associated with angiogenesis, we examined the effects of EGCG on vascular endothelial growth factor (VEGF) production by YCU-H891 HNSCC and MDA-MB-231 breast carcinoma cell lines, because we found that both of these cell lines display autocrine activation of transforming growth factor-alpha (TGF-alpha)/EGFR signaling and produce high levels of VEGF. Treatment with EGCG inhibited the constitutive activation of the EGFR, Stat3, and Akt in both cell lines. These changes were associated with inhibition of VEGF promoter activity and cellular production of VEGF. Mechanistic studies indicated that inhibition of Stat3, but not mitogen-activated protein kinase kinase (MEK)1 or phosphatidylinositol 3'-kinase (PI3K), significantly decreased VEGF promoter activity. However, the inhibitory effects of a dominant negative Stat3 on VEGF expression was not as strong as that produced by EGCG. An analysis of alternative pathways indicated that EGCG strongly inhibited the constitutive activation of NF-kappa B in both cell lines, and an NF-kappa B inhibitor strongly inhibited VEGF production. These results suggest that EGCG inhibits VEGF production by inhibiting both the constitutive activation of Stat3 and NF-kappa B, but not extracellular-signal-regulated kinase (ERK) or Akt, in these cells. Therefore, EGCG may be useful in treating HNSCC and breast carcinoma because it can exert both antiproliferative and antiangiogenic activities.
在最近一项针对头颈部鳞状细胞癌（HNSCC）细胞的研究中，我们发现表没食子儿茶素 - 3 - 没食子酸酯（EGCG），绿茶的一种主要生物活性成分，可抑制表皮生长因子受体（EGFR）的激活及相关信号通路。由于EGFR信号通路的激活与血管生成有关，我们检测了EGCG对YCU - H891 HNSCC和MDA - MB - 231乳腺癌细胞系血管内皮生长因子（VEGF）产生的影响，因为我们发现这两种细胞系均表现出转化生长因子 - α（TGF - α）/EGFR信号的自分泌激活并产生高水平的VEGF。用EGCG处理可抑制这两种细胞系中EGFR、Stat3和Akt的组成性激活。这些变化与VEGF启动子活性的抑制及细胞VEGF的产生相关。机制研究表明，抑制Stat3而非丝裂原活化蛋白激酶激酶（MEK）1或磷脂酰肌醇3'-激酶（PI3K）可显著降低VEGF启动子活性。然而，显性负性Stat3对VEGF表达的抑制作用不如EGCG产生的抑制作用强。对替代途径的分析表明，EGCG强烈抑制这两种细胞系中NF - κB的组成性激活，且NF - κB抑制剂强烈抑制VEGF的产生。这些结果表明，EGCG通过抑制这些细胞中Stat3和NF - κB的组成性激活而非细胞外信号调节激酶（ERK）或Akt来抑制VEGF的产生。因此，EGCG可能对治疗HNSCC和乳腺癌有用，因为它可发挥抗增殖和抗血管生成活性。
